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. 2022 Oct 28;378(6618):422-428.
doi: 10.1126/science.abq7871. Epub 2022 Oct 27.

Evolution and antiviral activity of a human protein of retroviral origin

John A Frank  1 , Manvendra Singh  1 , Harrison B Cullen  1 , Raphael A Kirou  1 , Meriem Benkaddour-Boumzaouad  2 , Jose L Cortes  2   3 , Jose Garcia Pérez  2   4 , Carolyn B Coyne  5 , Cédric Feschotte  1
Affiliations

Evolution and antiviral activity of a human protein of retroviral origin

John A Frank et al. Science. .

Abstract

Endogenous retroviruses are abundant components of mammalian genomes descended from ancient germline infections. In several mammals, the envelope proteins encoded by these elements protect against exogenous viruses, but this activity has not been documented with endogenously expressed envelopes in humans. We report that the human genome harbors a large pool of envelope-derived sequences with the potential to restrict retroviral infection. To test this, we characterized an envelope-derived protein, Suppressyn. We found that Suppressyn is expressed in human preimplantation embryos and developing placenta using its ancestral retroviral promoter. Cell culture assays showed that Suppressyn, and its hominoid orthologs, could restrict infection by extant mammalian type D retroviruses. Our data support a generalizable model of retroviral envelope co-option for host immunity and genome defense.

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Conflict of interest statement

Competing interests: The authors declare that they have no competing interests.

Figures

Fig. 1.
Fig. 1.. Expression profile of env-derived transcripts over a subset of human cell types.
(A-C) Heatmaps show envORF locus (rows) expression (log2 CPM > 1) in tissues (columns) (A), and stimulated immune (B) or HIV infected CD4+ T-cells (C). Bars above heatmaps denote sequencing strategy (A), tissue (A) or treatment (B, C) with the same color scheme in figures S1, S3, and S4. Rows and columns are ordered by hierarchical clustering of envORF expression. Significant envORF cluster enrichment was calculated by hypergeometric test. (B, C) Boxplots represent distribution of envORF expression levels relative to unstimulated (B) and Mock-infected cells (C). For (C), envORF expression is averaged across donors (n = 3) and normalized to mean expression of unstimulated cells (n = 6) (see fig. S4). (NS: not significant; ***p < 0.01; Wilcoxon rank-sum test)
Fig. 2.
Fig. 2.. Pluripotency and placentation regulatory factors drive SUPYN expression during fetal development.
(A) Violin plots represent single-cell SUPYN, SYN1 and ASCT2 expression in human preimplantation embryo (PrE: primitive endoderm, TrE: trophectoderm) and ESC. (B) Genome browser view of regulatory elements surrounding the SUPYN locus in hESCs, CTB, STB, BMP4-differentiated TB, and 293T cells. ChIP-seq profiles show indicated transcription factors and histone modifications. Shaded area highlights regions of active chromatin. (C) UMAP visualization of TB cell clusters (see fig S6). (D) Monocle2 pseudotime analysis of cell clusters in (C) illustrates developmental trajectory of CTBs to STB and EVTB. (E) Heatmap represents top 1000 differentially expressed genes (row) of single cells (column). Cells are ordered according to pseudotime progression in (D). SYN1, SUPYN, and ASCT2 were fetched from heatmap below. (F) Violin plots denote single-cell SUPYN expression in placental-cell lineages throughout indicated pregnancy stages. (G, H) Confocal microscopy of human preimplantation embryo (G) and placental villus explants (H) stained for SUPYN (green), OCT4 (red), ACTIN (red) and DAPI (blue). Trophectoderm (white arrows) and OCT4-expressing (red arrows) cells are highlighted in (G) subpanels (A-C). STBs are marked by arrowheads (H).
Fig. 3.
Fig. 3.. SUPYN confers resistance to RD114 env-mediated infection
(A) HIV-glycoprotein reporter virus production and infection assay approach (see Methods). (B-D) Proportion of GFP+ 293T, JEG3, Jar (B), 293T, H1-ESCs (C), and 293T, shSUPYN-Jar (D) cells infected with indicated reporter virus pseudotypes. (E) Relative infection rates of shSUPYN-Jar cells transfected with HA-tagged wild-type (WT-SP), rescue signal peptide (Resc-SP), or luciferase signal peptide (GPluc-SP) encoding SUPYN overexpression constructs. (F) Western Blot analysis (αHA, αGAPDH) of Jar-shSUPYN cell lysates transfected with indicated SUPYN overexpression constructs. (G-J) Relative infection rates of 293T cells transfected with unmodified RD114env (G), SUPYN (G, J), SMRVenv (J) or indicated HA-tagged protein overexpression plasmids and infected with indicated reporter viruses (top). (K) Representative Western blot analysis (αHA, αGAPDH, αASCT2) of 293T cell lysates following transfection with indicated constructs. Arrowheads and asterisks denote unglycosylated and glycosylated protein fragments respectively. (I) Model of SUPYN-dependent RDR infection restriction. SUPYN likely binds ASCT2 following secretion (I) or within the secretory compartment (ii). (n ≥ 3 with ≥ 2 technical replicates; ***adj. p < 0.001; **adj. p < 0.01; *adj. p < 0.05; ANOVA with Tukey HSD)
Fig. 4.
Fig. 4.. SUPYN emerged in a Catarrhine ancestor and has conserved antiviral activity in Hominoids.
(A) Consensus primate phylogeny with cartoon representation of SUPYN ORFs (blue box). Magenta boxes represent SUPYN ORF frameshifts. Red dashed lines denote conserved premature stop codon positions. Grey bars represent degraded HERVH48env sequence. Labeled triangle denotes ancestral lineage where HERVH48env was acquired. Colored circles indicate species used in (B) and (C). SUPYN dN/dS values are shown in box (*p < 0.05; LRT). (B, C) Relative infection rates and Western Blot of 293T cells transfected with primate (B) or ancestral (C) SUPYN-HA constructs and infected with HIV-RD114env. Relative infection rates were determined by normalizing GFP+ counts to empty vector. (n ≥ 3 with ≥ 2 technical replicates ***adj. p < 0.001; *adj. p < 0.05; ANOVA with Tukey HSD)
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Comment in

  • Stealing genes and facing consequences.
    Del Valle RP, McLaughlin RN Jr. Del Valle RP, et al. Science. 2022 Oct 28;378(6618):356-357. doi: 10.1126/science.ade4942. Epub 2022 Oct 27. Science. 2022. PMID: 36302006
  • Viral protection from viruses.
    Burgess DJ. Burgess DJ. Nat Rev Genet. 2023 Jan;24(1):2. doi: 10.1038/s41576-022-00557-7. Nat Rev Genet. 2023. PMID: 36414715 No abstract available.

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